The broad objectives are to apply and coordinate biochemical and engineering techniques to study platelet transport, adhesion, aggregation, and secretion in normal platelets and in patients with bleeding disorders. We plan to study: (1) the prostaglandin synthetic pathway, phospholipase A2 activation, and the response to thromboxane A2 in patients with release ('aspirin-like') defects, (2) the nature of the granule defect in storage pool disease, using the techniques of subcellular fractionation, electron microscopy, fluorescent staining and megakaryocyte studies, (3) the nature of the release defect in storage pool disease, (4) platelet secretion and the prostaglandin pathway in the fawn hooded (storage pool deficient) rat, (5) the biochemical basis of the impaired platelet function in DIC, immune-platelet injury, and myeloproliferative disorders, (6) the role of metal ions in secretion; whether there is some requirement for ADP in PGG2/TxA2 mediated platelet aggregtion; and mechanisms of collagen aggregation tht may be independent of ADP release and TxA2 synthesis, (7) in von Willebrand's disease, the content, characterization, and secretory pattern of factor VIII-antigen in platelets; the relationship between the hemostatic defect (bleeding time) and the von Willebrand factor; and patients with combined defects of factor VIII and platelet aggregation/secretion, (8) the various factors affecting platelet tranport, adhesion and thrombus formation on subendothelium and artificial surfaces including physical factors: (shear rate, platelet number and diffusivity, red cells), chemical factors (drugs, such as aspirin and dipyridamole, PGI2), surface factors (collagen, artificial surfaces, fibronectin) and plasma factors (factor VIII, fibrinogen, cold insoluble globulin, metal ions), (9) to examine further the nature of the platelet adhesion defect that we have reported in von Wellebrand's disease and (using platelets of patients with intrinsic platelet defects) to study the requirements for adhesion/aggregation, and secretion on subendothelium under conditions of controlled blood flow simulating that in the microcirculation.